The present invention encompasses novel sulfonylphenylpyrazole compounds useful in the treatment of cyclooxygenase-2 mediated diseases. More particularly, this invention concerns a method of inhibiting prostaglandin biosynthesis, particularly the induced prostaglandin endoperoxide H synthase (PGHS-2, cyclooxygenase-2, COX-2) protein.
The prostaglandins are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The discovery of two forms of prostaglandin endoperoxide H synthase that catalyze the oxidation of arachidonic acid leading to prostaglandin biosynthesis has resulted in renewed research to delineate the role of these two isozymes in physiology and pathophysiology. These isoenzymes PGHS-1 and PGHS-2 are more commonly referred to as cyclooxygenase-1 or COX-1 and cyclooxygenase-2 or COX-2. These isozymes have been shown to have different gene regulation and represent distinctly different prostaglandin biosynthesis pathways.
The PGHS-1 or COX-1 pathway is expressed constitutively in most cell types. This is an important xe2x80x9chousekeepingxe2x80x9d enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. It responds to produce prostaglandins that regulate acute events in vascular homeostasis and also has a role in maintaining normal stomach and renal function. The PGHS-2 or COX-2 pathway involves an induction mechanism which has been linked to inflammation, mitogenesis and ovulation phenomena. COX-2 is the inducible isoform associated with inflammation.
Prostaglandin inhibitors provide therapy for pain, fever, and inflammation, and are useful therapies, for example in the treatment of rheumatoid arthritis and osteoarthritis. The non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and fenamates inhibit both isozymes. Inhibition of the constitutive enzyme PGHS-1 results in gastrointestinal side effects including ulcers and bleeding and incidence of renal problems with chronic therapy. Inhibitors of the induced isozyme PGHS-2 may provide anti-inflammatory activity without the side effects of PGHS-1 inhibitors.
The problem of side-effects associated with NSAID administration has never completely been solved in the past. Enteric coated tablets and co-administration with misoprostol, a prostaglandin derivative, have been tried in an attempt to minimize stomach toxicity. It would be advantageous to provide compounds which are selective inhibitors of the induced isozyme PGHS-2.
The present invention discloses novel compounds which are selective inhibitors of PGHS-2.
The present invention discloses sulfonylphenylpyrazole compounds which are selective inhibitors of cyclooxygenase-2 (COX-2).
The compounds of the present invention are selected from the group having the formulas I, II, and III, below 
wherein
one of R1 and R2 is selected from the group consisting of: 
xe2x80x83wherein
R7 is selected from the group consisting of alkyl, amino, alkylamino, dialkylamino;
X4 is selected from the group consisting of xe2x80x94SO2xe2x80x94, xe2x80x94SO(NR8)xe2x80x94;
R8 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl;
R9 is selected from the group consisting of hydrogen and halogen; and
And the other of R1 and R2 is selected from the group consisting of hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro, and xe2x80x94Yxe2x80x94R10.
The Y group is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(R11)(R12)xe2x80x94, C(O)NR14xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NC(O)xe2x80x94, and xe2x80x94NR13xe2x80x94
R10 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),
R11, R12, and R13 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano; and
R14 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, aryl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, arylcarbonylalkyl, cycloalkylcarbonylalkyl, heterocycliccarbonylalkyl, alkylcarbonylalkyl, aryl(substituted alkyl), and arylalkyl;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, aryl(substituted alkyl), and arylalkyl;
X1 is selected from the group consisting of O, N(R4), wherein R4 is as previously described, and S;
X2 is selected from the group consisting of xe2x80x94Oxe2x80x94(CH2)n-, xe2x80x94Sxe2x80x94(CH2)nxe2x80x94, N(R4)xe2x80x94(CH2)nxe2x80x94, wherein n is 0 or 1 and R4 is as previously described, xe2x80x94Oxe2x80x94CH(Rxe2x80x2)xe2x80x94, xe2x80x94Sxe2x80x94CH(Rxe2x80x2)xe2x80x94, and xe2x80x94N(R4)xe2x80x94CH(Rxe2x80x2)xe2x80x94;
X3 is absent, or is selected from the group consisting of xe2x80x94CH2xe2x80x94, and xe2x80x94C(R15)(R16)xe2x80x94, wherein R15 and R16 are independently selected from the group consisting of hydrogen and alkyl;
R5 and R6 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, aryl(substituted alkyl), and arylalkyl, or R5 and R6 are taken together with the atoms to which they are attached to form a 5 to 7 membered ring, optionally aromatic, and optionally containing one or two heteroatoms selected from O, N, and S, and optionally substituted with 1 to 2 groups selected from alkyl, hydroxy, halogen, oxo, haloalkyl, cyano and nitro;
the dashed bond represents an optional double bond;
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The present invention discloses sulfonylphenylpyrazole compounds which are cyclooxygenase (COX) inhibitors and are selective inhibitors of cyclooxygenase-2 (COX-2).
The compounds of the present invention are selected from the group having the formulas I, II, and III, below 
wherein
one of R1 and R2 is selected from the group consisting of: 
xe2x80x83wherein
R7 is selected from the group consisting of alkyl, amino, alkylamino, dialkylamino;
X4 is selected from the group consisting of xe2x80x94SO2xe2x80x94, xe2x80x94SO(NR8)xe2x80x94;
R8 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl;
R9 is selected from the group consisting of hydrogen and halogen; and
And the other of R1 and R2 is selected from the group consisting of hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro, and xe2x80x94Yxe2x80x94R10.
The Y group is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(R11)(R12)xe2x80x94, C(O)NR14xe2x80x94, xe2x80x94C(O)xe2x80x94, C(O)Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NC(O)xe2x80x94, and xe2x80x94NR13xe2x80x94
R10 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),
R11, R12, and R13 are independently selected from the group. consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano; and
R14 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, aryl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, arylcarbonylalkyl, cycloalkylcarbonylalkyl, heterocycliccarbonylalkyl, alkylcarbonylalkyl ,aryl(substituted alkyl), and arylalkyl;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, aryl(substituted alkyl), and arylalkyl;
X1 is selected from the group consisting of O, N(R4), wherein R4 is as previously described, and S;
X2is selected from the group consisting of xe2x80x94Oxe2x80x94(CH2)n-, xe2x80x94Sxe2x80x94(CH2)nxe2x80x94, N(R4)xe2x80x94(CH2)nxe2x80x94, wherein n is 0 or 1 and R4 is as previously described, xe2x80x94Oxe2x80x94CH(Rxe2x80x2)xe2x80x94, xe2x80x94Sxe2x80x94CH(Rxe2x80x2)xe2x80x94, and xe2x80x94N(R4)xe2x80x94CH(Rxe2x80x2)xe2x80x94;
X3 is absent, or is selected from the group consisting of xe2x80x94CH2xe2x80x94, and xe2x80x94C(R15)(R16)xe2x80x94, wherein R15 and R16 are independently selected from the group consisting of hydrogen and alkyl;
R5 and R6 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, aryl(substituted alkyl), and arylalkyl, or R5 and R6 are taken together with the atoms to which they are attached to form a 5 to 7 membered ring, optionally aromatic, and optionally containing one or two heteroatoms selected from O, N, and S, and optionally substituted with 1 to 2 groups selected from alkyl, hydroxy, halogen, oxo, haloalkyl, cyano and nitro;
the dashed bond represents an optional double bond;
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In another embodiment of the present invention compounds are selected from the group having the formulas I, II, and III, wherein
R1 s selected from the group consisting of: 
xe2x80x83wherein
R7is selected from the group consisting of alkyl, amino, alkylamino, dialkylamino;
X4 is selected from the group consisting of xe2x80x94SO2xe2x80x94, xe2x80x94SO(NR8)xe2x80x94;
R8 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl;
R9 is selected from the group consisting of hydrogen and halogen; and
R2 is selected from the group consisting of hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, amido, amidoalkyl, halo alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic (alkyl), cyano, nitro, and xe2x80x94Yxe2x80x94R10.
The Y group is selected from the group consisting of, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(R11)(R12)xe2x80x94, C(O)NR14xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NC(O)xe2x80x94, and xe2x80x94NR13xe2x80x94
R10 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic (alkyl),
R11, R12, and R13 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano; and
R14 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic (alkyl), and cyano;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, arylcarbonylalkyl, cycloalkylcarbonylalkyl, heterocycliccarbonylalkyl, alkylcarbonylalkyl, aryl(substituted alkyl), and arylalkyl;
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, aryl(substituted alkyl), and arylalkyl;
X2 is selected from the group consisting of xe2x80x94O, N(R4), wherein R4 is as previously described, and S;
X2 is selected from the group consisting of xe2x80x94Oxe2x80x94(CH2)n-, xe2x80x94Sxe2x80x94(CH2)nxe2x80x94, N(R4)xe2x80x94(CH2)nxe2x80x94, wherein n is 0 or 1 and R4 is as previously described, xe2x80x94Oxe2x80x94CH(Rxe2x80x2)xe2x80x94, xe2x80x94Sxe2x80x94CH(Rxe2x80x2)xe2x80x94, and xe2x80x94N(R4)xe2x80x94CH(Rxe2x80x2)xe2x80x94;
X3 is absent, or is selected from the group consisting of xe2x80x94CH2xe2x80x94, and xe2x80x94C(R15)(R16)xe2x80x94, wherein R15 and R16 are independently selected from the group consisting of hydrogen and alkyl;
R5 and R6 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocycloalkyl, heterocyclic, aryl(substituted alkyl), and arylalkyl, or R5 and R6 are taken together with the atoms to which they are attached to form a 5 to 7 membered ring, optionally aromatic, and optionally containing one or two heteroatoms selected from O, N, and S, and optionally substituted with 1 to 2 groups selected from alkyl, hydroxy, halogen, oxo, haloalkyl, cyano and nitro;
the dashed bond represents an optional double bond;
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
In one embodiment of the present invention are compounds represented by the following structural formula I, wherein X2, X3, R1, R2, R5, and R6 are as previously described.
In another embodiment of the present invention are compounds represented by the following structural formula II, wherein X1, R1, R2, R3, and R4 are as previously described.
In an additional embodiment of the present invention are compounds represented by the following structural formula III, wherein X1, R1, R2, R3, and R4 are as previously described.
In another embodiment of the present invention are compounds having formula II wherein X1 is oxygen, R4 is alkyl, R3 is selected from the group consisting of arylcarbonylalkyl, cycloalkylcarbonylalkyl, heterocycliccarbonylalkyl, and alkylcarbonylalkyl, R2 is substituted and unsubstituted aryl, and R1 is as defined above.
In another embodiment of the present invention are compounds having formula I wherein X2 is oxygen, R1 and R2 are as defined above, X3 is absent or xe2x80x94CH2xe2x80x94, and R5 and R6 form a 5 to 7 membered aromatic and non-aromatic carbocyclic ring, said carbocyclic ring optionally being mono, di, or trisubstituted with halogen.
Another embodiment of the present invention are compounds having formula I wherein X2 is oxygen, R1 and R2 are as defined above, X3 is absent or xe2x80x94CH2xe2x80x94, R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, cyano, and aryl.
Preferred compounds of the present invention include:
3-(4-Fluorophenyl)-2-(4-(methylsulphonyl)phenyl)-5H-pyrazolo[1,5-a][3,1]-benzoxazine;
2-[(1-Ethyl-4-(4-fluorophenyl)-5-(4-(methylsulphonyl)phenyl)-1H-pyrazol-3-yl)oxy]-1-(2-thienyl)ethan-1-one;
1-[(1-Ethyl-4-(4-fluorophenyl)-5-(4-(methylsulphonyl)phenyl)-1H-pyrazol-3-yl)oxy]-3,3-dimethylbutan-2-one;
1-[(1-Ethyl-4-(4-fluorophenyl)-5-(4-(aminosulphonyl)phenyl)-1H-pyrazol-3-yl)oxy]-3,3-dimethylbutan-2-one;
3-(4-Fluorophenyl)-2-(4-(methylsulphonyl)phenyl)-5,6,7,8-tetrahydropyrazolo[5-b][1,3]benzoxazole;
3-(Tert-butyl)-7-(4-fluorophenyl)-6-(4-(aminosulphonyl)phenyl)pyrazolo[5,1-b][1,3]-oxazole;
7-(4-Fluorophenyl)-3-methyl-6-(4-(aminosulphonyl)phenyl)pyrazolo[5,1-b][1,3]oxazole-2-carbonitrile;
3-Ethyl-7-(4-fluorophenyl)-6-(4-(methylsulphonyl)phenyl)pyrazolo[5,1-b][1,3]oxazole;
3-Ethyl-7-(4-fluorophenyl)-6-(4-(aminosulphonyl)phenyl)pyrazolo[5,1-b][1,3]oxazole;
6-Chloro-3-(4-fluorophenyl)-2-(4-(methylsulphonyl)phenyl)-5H-pyrazolo[1,5-a][3,1]benzoxazine;
3-(4-Fluorophenyl)-2-(4-aminosulphonyl)phenyl)-5H-pyrazolo[1,5-a][3,1]benzoxazine; and
2,6-Bis(4-fluorophenyl)-3-methyl-7-(4-(methylsulphonyl)phenyl)pyrazolo[5,1-b][1,3]oxazole;
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof
Abbreviations which have been used in the embodiments, descriptions of the scheme and the examples that follow are:
The terms xe2x80x9cloweralkylxe2x80x9dor xe2x80x9calkylxe2x80x9d as used herein refer to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term xe2x80x9calkylaminoxe2x80x9d as used herein refers to R51NHxe2x80x94 wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein refers to R56R57Nxe2x80x94 wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a monovalent group derived from a hydrocarbon containing at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1-methyl-2-buten-1-yl and the like.
The term xe2x80x9calkylenexe2x80x9d denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to R41Oxe2x80x94 wherein R41 is a loweralkyl group, as defined above. Examples of alkoxy include, but are not limited to, ethoxy, tert-butoxy, and the like.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkoxy group as previously defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
The term xe2x80x9calkylcarbonylalkylxe2x80x9d as used herein refers to R62C(O)R63xe2x80x94 wherein R62 is alkyl and R63 is an alkyl radical.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl, and the like.
The term xe2x80x9camido,xe2x80x9d as used herein, refers to a xe2x80x94NR9R10 group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of amido include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, benzylaminocarbonyl, and the like.
The term xe2x80x9camidoalkyl,xe2x80x9d as used herein, refers to an amido group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of amidoalkyl include, but are not limited to, aminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl, 3-(benzylaminocarbonyl)propyl, and the like.
The term xe2x80x9caminocarbonylxe2x80x9d as used herein refers to H2Nxe2x80x94C(O)xe2x80x94.
The term xe2x80x9caminocarbonylalkylxe2x80x9d as used herein refers to H2Nxe2x80x94C(O)R64xe2x80x94 wherein R64 is alkyl as defined herein.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, S tetrahydronaphthyl, naphthyridinyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9carylalkylxe2x80x9d as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
The term xe2x80x9carylalkylaminoxe2x80x9d as used herein refers to R55NHxe2x80x94 wherein R55 is an arylalkyl group, for example benzylamino and the like.
The term xe2x80x9carylaminoxe2x80x9d as used herein refers to R53NHxe2x80x94 wherein R53 is an aryl group, for example, anilino, and the like.
The term xe2x80x9carylcarbonylalkylxe2x80x9d as used herein refers to R54C(O)R56xe2x80x94 wherein R54 is an aryl group and R56 is alkylene.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccycloalkenyl,xe2x80x9d as used herein, refers to a cyclic hydrocarbon containing from 3 to 8 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of cycloalkenyl include, but are not limited to, cyclohexene, 1-cyclohexen-2-yl, 3,3-dimethyl-1-cyclohexene, cyclopentene, cycloheptene, and the like.
The cycloalkenyl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkynyl, amido, amidoalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, sulfamylalkyl, xe2x80x94NR9R10, (NR9R10)alkyl.
The term xe2x80x9ccycloalkenylalkyl,xe2x80x9d as used herein, refers to a cycloalkenyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkenylalkyl include, but are not limited to, (2,6,6-trimethyl-1-cyclohexen-1-yl)methyl, 1-cyclohexen-1-ylmethyl, 2-(2-cyclohepten-1-yl)ethyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
The term xe2x80x9ccycloalkylcarbonylalkylxe2x80x9d as used herein refers to a R57C(O)R58xe2x80x94 wherein R57 is a cycloalkyl group as defined herein and R58 is alkylene.
The term xe2x80x9cdiarylaminoxe2x80x9d as used herein refers to R60R61Nxe2x80x94 wherein R60 and R61 are both aryl as defined herein.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein refers to I, Br, Cl or F.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
The terms xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one nitrogen and one sulfur atom; or one nitrogen and one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered ring have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or benzothienyl and the like). Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (xe2x95x90O), alkylimino (R*N=wherein R* is a loweralkyl group), amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, xe2x80x94COOH, xe2x80x94SO3H and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected.
The term xe2x80x9cheterocyclic(alkyl)xe2x80x9d as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
The term xe2x80x9cheterocycliccarbonylalkylxe2x80x9d as used herein refers to a heterocycle as defined herein appended to the parent molecular moiety through a carbonylalkyl (Heterocycle-C(O)R64xe2x80x94), wherein R64 is alkylene.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, 2-hydroxy-1,1-dimethylethyl, 3-hydroxy-1,1-dimethylpropyl, and the like.
The term xe2x80x9cnitroxe2x80x9d as used herein refers to xe2x80x94NO2.
The term xe2x80x9csubstituted alkyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, substituted with 2, 3, or 4 substituents selected from alkoxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, amido, aryl, arylalkoxycarbonyl, arylcarbonyloxy, aryloxycarbonyl, xe2x80x94CF3, cyano, cycloalkyl, halo, haloalkoxy, heterocycle, hydroxy, sulfamyl, alkylsulfonyl, arylsulfonyl, and xe2x80x94NR9R10, as defined herein. Representative examples of substituted alkyl include, but are not limited to, 3-cyano-1,1-difluoropropyl, 1,1-dichloro-3-cyanopropyl, 1,1-bis(trifluoromethyl)-3-cyano-2-propyl, and the like.
Preparation of the Compounds of the Invention
The compounds and processes of the present invention will be better understood in connection with the following synthetic Schemes 1-9 which illustrate the methods by which the compounds of the invention may be prepared.
Compounds of the invention may be prepared as described in the following Schemes 1-8. Compounds having formula II wherein X1 is O may be prepared according to Scheme 1. In one process therein, an appropriate acid chloride compound 1, wherein R1 is as previously described, and an appropriate ester compound 2, wherein R2 is as previously described, are reacted to provide xcex2-ketoester 3. This reaction may be performed in an appropriate solvent, such as THF, DME, Et2O, dioxane, etc, for example in the presence of strong base like LDA, TMS2NLi, tBuOK, etc, and at a temperature from about xe2x88x9278xc2x0 C. to about 0xc2x0 C. for a period of about 1 hour to about 5 hours or until the reaction is complete. In those instances wherein R2 is an amino group, it may be necessary to use an amino-protected precursor compound in order to prevent undesirable side reactions. Such amino-protecting groups are well known to those skilled in the art. Compound 3 is then treated with hydrazine in the presence of slight excess of an acid, such as acetic acid, for example, to provide the 3-hydroxypyrazole compound 7. Compound 7 is a compound of Formula II wherein R4 is H. 
In an alternate approach; also outlined in Scheme 1, the reaction of an appropriate Grignard compound 4, wherein R2 is as previously described or is a suitably protected precursor thereof, with a properly derivatized carboxylic acid 5, such as a nitrile, N-methoxy-N-methylamide or imidazolide, for example, affords the intermediate keto compound 6. Reaction of compound 6 with ethyl cyanoformate in the presence of base, such as for example TMS2Nli, LDA, tBuOK, and the like, provides the xcex2-ketoester 3, which may be converted into 3-hydroxypyrazole compound 7 as described above.
Compound 7 may be treated with, an appropriate R3-halogen derivative, wherein R3 is a previously described, to give the O-alkylderivative 8. This reaction may be performed in an aprotic solvent, such as DMF or DMSO, for example, from about 25xc2x0 C. to about 50xc2x0 C. in the presence of K2CO3 or another suitable base, such as NaH, Na2CO3, Et3N, and the like. Compound 8 can be alkylated again with the same R3-halogen compound or with another R4-halogen compound, wherein R4 is also as previously described, to provide the desired 1,3-dialkylated compound 9, which is a compound of formula II, wherein X1 is O. 
In accordance with Scheme 2 are prepared compounds of formula II wherein X1 is N(R4). In the case wherein R4 is H, the reaction of acid chloride 1, wherein R1 is as previously described, with an appropriate nitrile 10, wherein R2 is as previously described, in the presence of a strong base such as TMS2NLi, LDA, tBuOK, and the like, or a similar strong base, for example, leads to the xcex2-ketonitrile 11, which then can be treated with hydrazine in the presence of slight excess of acetic acid as described in Scheme 2 to provide the 3-aminopyrazole compound 12. Compound 12 can be reductively alkylated under standard conditions using reagents such as MeOH/AcOH or NaBH3CN or the like with aldehyde or ketone to the provide 3-N-alkyl derivative 13 which is then alkylated with R4-halogen using conditions described in Scheme 1 to afford 1,3-dialkylated compound of formula II, wherein X1 is NH. Compounds of formula II, wherein X1 is N(R4) wherein R4 is not H can be prepared from compounds 13 or 14 by reductive alkylation in DMF, acetone or the like, in the presence of a base such as K2CO3, NaH, or the like, from about room temperature to 75xc2x0 C. or higher. 
Scheme 3 describes the preparation of compounds wherein X1 is S. The 3-hydroxypyrazole 7 can be reacted with triflic chloride in the presence of pyridine or any anhydrous base to provide triflate 15. The reaction may be performed at temperatures from xe2x88x9210xc2x0 C. to about room temperature. The compound 15 is reacted directly with mercaptide R3SNa, wherein R3 is as previous described, to provide 3-alkylthiopyrazole 18. Alternately, the triflate 15 is first transformed into isothiourea derivative 16 by reaction with thiourea in the presence of nickel catalyst. Compound 16 is then hydrolyzed to the 3-mercaptoderivative 17, which may be alkylated with R3-halogen, as described in Scheme 1, to give compound 18. Compound 18 is a compound of formula II wherein X1 is S and R4 is H. Alkylation of derivative 18 with R4-halogen under similar conditions provides additional compounds of formula II wherein X1 is S and R4 is not H. 
Compounds of the invention having formula III wherein X1 is O may be prepared according to Scheme 4. The previously described compound 3 is treated with monosubstituted hydrazine R4xe2x80x94NHNH2, in the presence of slight excess of an acid, such as acetic acid, for example, to prepare the 3-hydroxy compound 20. Compound 20 is then treated with an appropriate R3-halogen in DMF or DMSO in the presence of base such as K2CO3, for example, to give the desired compound 21, which is a compound of formula III wherein X1 is O. 
The compounds of formula II wherein X1 is NH can be prepared as outlined in Scheme 5, starting with the previously described nitrile compound 11 and applying conditions described in Scheme 4. Reaction of compound 11 with R4xe2x80x94NHNH2 in the presence of acid gives the derivative 22 which may be then alkylated with R3-halogen to afford compound 23 which is a compound of formula II wherein X1 is NH.
Compounds of the invention having formula II wherein X1 is S may be prepared as described in Scheme 6. The 3-hydroxypyrazole 20, described in Scheme 4, can be transformed into triflate 24 as provided in Scheme 3. The compound 24 may directly react with mercaptide R3SNa to provide the desired compound 27. Alternately, triflate 24 can be first transformed into isothiouronium salt 25 followed by hydrolysis and alkylation with R3-halogen to give the compound of formula II wherein X1 is S. 
Compounds of the invention having formula I may be prepared according to Scheme 7. For compounds of formula I wherein X3 is absent, X2 is xe2x80x94Oxe2x80x94(CH2)n-, xe2x80x94Sxe2x80x94(CH2)nxe2x80x94, N(R4)xe2x80x94(CH2)nxe2x80x94, and n is 0, previously described compounds 7, 12, 13, 17 can be treated with an alpha-halogenated ketone in the presence of K2CO3 in DMF or DMSO at about 50xc2x0 C. to provide 3-alkylated derivative 28. Refluxing of the solution of compound 28 in toluene-AcOH mixture in the presence of p-tolunesulphonic acid or pyridinium p-toluenesulphonate gives the desired compounds 29, which are compounds of formula I. Alternately, the compounds may be prepared by reaction first with ortho-bromo- or chloro-benzyl bromide(or chloride) derivatives in the presence of K2CO3 in DMF at 50xc2x0 C. to provide compounds 30. These compounds 30 may be reacted via intramolecullar Ullman cyclisation in the presence Cu in pyridine or CuI in DMF to afford the desired compounds 31, which are compounds of formula I.
Alternately, as described in Scheme 8, to prepare compounds of formula I wherein X3 is absent, X2 is xe2x80x94Oxe2x80x94(CH2)n-, xe2x80x94Sxe2x80x94(CH2)nxe2x80x94, N(R4)xe2x80x94(CH2)nxe2x80x94, and n is 1, previously described compounds 7, 12, 13, 17 can be treated with ortho-bromo- or chloro-phenylethyl bromide(or chloride) compounds in the presence of K2CO3 in DMF at about 80xc2x0 C. to provide compounds 32. The cyclization of compounds 32 to give compounds 33 requires strong acid such as polyphosphoric acid or methanesulphonic acid, for example.
For compounds of formula I wherein X3 is absent and X2 is xe2x80x94OCH(Rxe2x80x2), xe2x80x94SCH(Rxe2x80x2), xe2x80x94NHCH(Rxe2x80x2), or xe2x80x94NR3CH(Rxe2x80x2) previously described compounds 7, 12, 13, 17 can be treated with appropriately substituted ortho-bromo- or chloro-phenylethyl bromide(or chloride) compounds in the presence of K2CO3 in DMF at about 80xc2x0 C. to provide compounds 34. The cyclization of compounds 34to give compounds 35 requires strong acid such as polyphosphoric acid or methanesulphonic acid, for example. 
Compounds of the invention having formula I wherein X2 is as described previously and X3 is C(R15)(R16) may be prepared according to Scheme 9. The previously described compounds 7, 12, 13, 17 can be treated at 50xc2x0 C. with 1,4-dihalogene substituted compound 36 to give the desired compounds 37.